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Cureus Sep 2023Myasthenia gravis (MG) is a neuromuscular junction disorder involving autoantibodies affecting the postsynaptic muscle membrane. We report an 81-year-old man who...
Myasthenia gravis (MG) is a neuromuscular junction disorder involving autoantibodies affecting the postsynaptic muscle membrane. We report an 81-year-old man who presented to the emergency department with three days of left facial droop, who later developed worsening bilateral ptosis, cervical weakness, dysphagia, and dysarthria following an assessment for Bell's palsy. Ultimately, he was diagnosed with MG. This patient's presentation was atypical and challenging. Specifically, the patient had droopy eyelids from a redundancy of skin and an anatomical neck droop, non-specific findings in older adults, which obscured the development of bilateral ptosis and cervical weakness, a classic sign of bulbar disease. The patient also presented with unilateral facial weakness, a rare finding in MG and concerning stroke in the elderly population. Our aim is to discuss the challenges of identifying MG in older populations and to discuss pharmacological challenges in assessing elderly patients with suspected bulbar palsies.
PubMed: 37809196
DOI: 10.7759/cureus.44737 -
Molecular & Cellular Proteomics : MCP Nov 2023The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is a key node in the regulation of...
The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is a key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the hippocampal PSD proteome and phosphoproteome in mice following four different types of experience. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated from individual mice to investigate molecular mechanisms underlying experience-dependent remodeling of synapses. We developed a new strategy to identify and quantify the relatively low level of site-specific phosphorylation of PSD proteome from the hippocampus, by using a modified iTRAQ-based TiSH protocol. In the PSD, we identified 3938 proteins and 2761 phosphoproteins in the sequential strategy covering a total of 4968 unique protein groups (at least two peptides including a unique peptide). On the phosphoproteins, we identified a total of 6188 unambiguous phosphosites (75%
Topics: Mice; Animals; Proteome; Membrane Proteins; Nerve Tissue Proteins; Hippocampus; Synapses; Peptides; Phosphoproteins; Disks Large Homolog 4 Protein
PubMed: 37806341
DOI: 10.1016/j.mcpro.2023.100661 -
Molecular Medicine Reports Nov 2023Blume has been widely used to treat various central and peripheral nerve diseases, and Para‑hydroxybenzaldehyde (PHBA) is one of the indicated components suggested to...
Blume has been widely used to treat various central and peripheral nerve diseases, and Para‑hydroxybenzaldehyde (PHBA) is one of the indicated components suggested to provide a neuroprotective effect. In our previous, it was shown that PHBA protected mitochondria against cerebral ischemia‑reperfusion (I/R) injury in rats. In the present study, how PHBA regulated the metabolic mechanism in blood following cerebral I/R was assessed to identify an effective therapeutic target for the prevention and treatment of ischemic stroke (IS). First, a rat model of cerebral ischemia‑reperfusion injury was established via middle cerebral artery occlusion/reperfusion (MCAO/R). The therapeutic effect of PHBA on brain I/R was evaluated by assessing the neurological function score, triphenyl tetrazolium chloride, hematoxylin and eosin, and Nissl staining. Next, a non‑targeted metabolomic based on high‑performance liquid chromatography quadrupole time‑of‑flight mass spectrometry was established to identify differential metabolites. Finally, a targeted metabolic spectrum was analyzed and the potential therapeutic targets were verified by Western blotting. The results showed that the neurological function score, cerebral infarction area, hippocampal morphology, and the number of neurons in the PHBA group were significantly improved compared with the model group. Metabonomic analysis showed that 13 different metabolites were identified between the model and PHBA group, which may be involved in the 'tricarboxylic acid cycle', 'glutathione metabolism', and 'mutual transformation of pentose and glucuronates', amongst others. Among these, the levels of the most significant differential metabolite, dGMP, decreased significantly following PHBA treatment. Western blotting was used to verify the expression of membrane‑associated guanosine kinase PSD‑95 and the subunit of glutamate AMPA receptor GluA1, which significantly increased after PHBA treatment. In addition, it was also found that PHBA increased the expression of the light chain‑3 protein and autophagy effector protein 1, whilst the expression of sequestosome‑1 decreased, indicating that PHBA promoted autophagy. Similarly, in TUNEL staining and detection of apoptosis‑related proteins, it was found that MCAO/R upregulated the expression of Bax and cleaved‑caspase‑3 whilst downregulating the expression of Bcl‑2 and increasing the apoptosis of hippocampal neurons; PHBA reversed this situation. These results suggest that cerebral I/R causes postsynaptic dysfunction by disrupting the interaction between PSD‑95 and AMPARs, and the inhibition of the autophagy system eventually leads to the apoptosis of hippocampal neurons.
Topics: Rats; Animals; Ischemic Attack, Transient; Brain Ischemia; Benzaldehydes; Apoptosis; Infarction, Middle Cerebral Artery; Apoptosis Regulatory Proteins; Reperfusion Injury; Neuroprotective Agents
PubMed: 37800608
DOI: 10.3892/mmr.2023.13111 -
BioRxiv : the Preprint Server For... Sep 2023Dendritic spines are small protrusions on dendrites in neurons and serve as sites of postsynaptic activity. Some of these spines contain smooth endoplasmic reticulum...
UNLABELLED
Dendritic spines are small protrusions on dendrites in neurons and serve as sites of postsynaptic activity. Some of these spines contain smooth endoplasmic reticulum (SER), and sometimes an even further specialized SER known as the spine apparatus (SA). In this work, we developed a stochastic spatial model to investigate the role of the SER and the SA in modulating Ca dynamics. Using this model, we investigated how ryanodine receptor (RyR) localization, spine membrane geometry, and SER geometry can impact Ca transients in the spine and in the dendrite. Our simulations found that RyR opening is dependent on where it is localized in the SER and on the SER geometry. In order to maximize Ca in the dendrites (for activating clusters of spines and spine-spine communication), a laminar SA was favorable with RyRs localized in the neck region, closer to the dendrite. We also found that the presence of the SER without the laminar structure, coupled with RyR localization at the head, leads to higher Ca presence in the spine. These predictions serve as design principles for understanding how spines with an ER can regulate Ca dynamics differently from spines without ER through a combination of geometry and receptor localization.
HIGHLIGHTS
1RyR opening in dendritic spine ER is location dependent and spine geometry dependent. Ca buffers and SERCA can buffer against runaway potentiation of spines even when CICR is activated. RyRs located towards the ER neck allow for more Ca to reach the dendrites. RyRs located towards the spine head are favorable for increased Ca in spines.
PubMed: 37790389
DOI: 10.1101/2023.09.22.558941 -
Molecular Neurobiology Mar 2024Long non-coding RNAs (lncRNAs) are a recently discovered group of non-coding RNAs that play a crucial role in the regulation of various human diseases, especially in the...
Long non-coding RNAs (lncRNAs) are a recently discovered group of non-coding RNAs that play a crucial role in the regulation of various human diseases, especially in the study of nervous system diseases which has garnered significant attention. However, there is limited knowledge on the identification and function of lncRNAs in hepatolenticular degeneration (HLD). The objective of this study was to identify novel lncRNAs and determine their involvement in the networks associated with HLD. We conducted a comprehensive analysis of RNA sequencing (RNA-seq) data, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and computational biology to identify novel lncRNAs and explore their potential mechanisms in HLD. We identified 212 differently expressed lncRNAs, with 98 upregulated and 114 downregulated. Additionally, 32 differently expressed mRNAs were found, with 15 upregulated and 17 downregulated. We obtained a total of 1131 pairs of co-expressed lncRNAs and mRNAs by Pearson correlation test and prediction and annotation of the lncRNA-targeted miRNA-mRNA network. The differential lncRNAs identified in this study were found to be involved in various biological functions and signaling pathways. These include translational initiation, motor learning, locomotors behavior, dioxygenase activity, integral component of postsynaptic membrane, neuroactive ligand-receptor interaction, nuclear factor-kappa B (NF-κB) signaling pathway, cholinergic synapse, sphingolipid signaling pathway, and Parkinson's disease signaling pathway, as revealed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Six lncRNAs, including XR_001782921.1 (P < 0.01), XR_ 001780581.1 (P < 0.01), ENSMUST_00000207119 (P < 0.01), XR_865512.2 (P < 0.01), TCONS_00005916 (P < 0.01), and TCONS_00020683 (P < 0.01), showed significant differences in expression levels between the model group and normal group by RT-qPCR. Among these, four lncRNAs (TCONS_00020683, XR_865512.2, XR_001780581.1, and ENSMUST00000207119) displayed a high degree of conservation. This study provides a unique perspective for the pathogenesis and therapy of HLD by constructing the lncRNA-miRNA-mRNA network. This insight provides a foundation for future exploration in this field.
Topics: Humans; MicroRNAs; RNA, Messenger; RNA, Long Noncoding; Hepatolenticular Degeneration; Brain; Gene Regulatory Networks
PubMed: 37759104
DOI: 10.1007/s12035-023-03631-1 -
Brain Research Dec 2023Epileptic activity is known to cause a lowering of intraneuronal pH, which has been suggested to serve as a feedback signal to terminate seizures. The mechanism of such...
Epileptic activity is known to cause a lowering of intraneuronal pH, which has been suggested to serve as a feedback signal to terminate seizures. The mechanism of such signaling is unclear, but likely involves an altered function of several types of ligand- and voltage-gated channels in postsynaptic membranes caused by increasing cytosolic and extracellular [H]. In addition, axonal conduction properties may be altered by endogenous pH signals, but this has not been investigated. In the present study, we have recorded the axonal compound action potential (fiber volley) in hippocampal slices in the presence of glutamatergic and GABAergic antagonists. During high-frequency stimulation (HFS) of the Schaffer collaterals, the fiber volley was depressed and its latency from stimulus to peak increased. In the CA1 stratum radiatum these changes were enhanced when the carbonic anhydrase inhibitor acetazolamide (1 mM) was co-perfused. The enhancing effect of acetazolamide was absent after lowering of [Ca] in the perfusion medium. Acetazolamide had no detectable effect on HFS-evoked fiber volleys recorded from a more proximal site along the Schaffer collaterals (at the CA2-CA3 border) or from axons in the alveus of CA1. Intracellular acidification imposed by washout of NHCl (5 mM) had qualitatively similar effects on fiber volleys evoked at low frequency as those observed with acetazolamide during HFS in CA1 stratum radiatum. The results suggest that carbonic anhydrase-dependent pH regulation counteracts activity-induced reduction of the excitability of Schaffer collateral axons in CA1. A possible influence from local synaptic terminals on this effect is discussed.
Topics: Acetazolamide; Action Potentials; Hippocampus; Axons; CA1 Region, Hippocampal; Electric Stimulation
PubMed: 37748571
DOI: 10.1016/j.brainres.2023.148604 -
BMC Genomics Sep 2023In Alzheimer's Disease (AD) and other dementias, hippocampal synaptic dysfunction and loss contribute to the progression of memory impairment. Recent analysis of human...
In Alzheimer's Disease (AD) and other dementias, hippocampal synaptic dysfunction and loss contribute to the progression of memory impairment. Recent analysis of human AD transcriptomes has provided a list of gene candidates that may serve as drivers of disease. One such candidate is the membrane protein TMEM184B. To evaluate whether TMEM184B contributes to neurological impairment, we asked whether loss of TMEM184B in mice causes gene expression or behavior alterations, focusing on the hippocampus. Because one major risk factor for AD is age, we compared young adult (5-month-old) and aged (15-month-old) wild type and Tmem184b-mutant mice to assess the dual contributions of age and genotype. TMEM184B loss altered expression of pre- and post-synaptic transcripts by 5 months and continued through 15 months, specifically affecting genes involved in synapse assembly and neural development. Wnt-activated enhancer elements were enriched among differentially expressed genes, suggesting an intersection with this pathway. Few differences existed between young adult and aged mutants, suggesting that transcriptional effects of TMEM184B loss are relatively constant. To understand how TMEM184B disruption may impact behaviors, we evaluated memory using the novel object recognition test and anxiety using the elevated plus maze. Young adult Tmem184b-mutant mice show normal object discrimination, suggesting a lack of memory impairment at this age. However, mutant mice showed decreased anxiety, a phenotype seen in some neurodevelopmental disorders. Taken together, our data suggest that TMEM184B is required for proper synaptic gene expression and anxiety-related behavior and is more likely to be linked to neurodevelopmental disorders than to dementia.
Topics: Humans; Young Adult; Animals; Mice; Infant; Gene Regulatory Networks; Alzheimer Disease; Genotype; Hippocampus; Membrane Proteins
PubMed: 37730546
DOI: 10.1186/s12864-023-09676-9 -
Cellular and Molecular Life Sciences :... Sep 2023Recently, the localization of amyloid precursor protein (APP) into reversible nanoscale supramolecular assembly or "nanodomains" has been highlighted as crucial towards...
Recently, the localization of amyloid precursor protein (APP) into reversible nanoscale supramolecular assembly or "nanodomains" has been highlighted as crucial towards understanding the onset of the molecular pathology of Alzheimer's disease (AD). Surface expression of APP is regulated by proteins interacting with it, controlling its retention and lateral trafficking on the synaptic membrane. Here, we evaluated the involvement of a key risk factor for AD, PICALM, as a critical regulator of nanoscale dynamics of APP. Although it was enriched in the postsynaptic density, PICALM was also localized to the presynaptic active zone and the endocytic zone. PICALM colocalized with APP and formed nanodomains with distinct morphological properties in different subsynaptic regions. Next, we evaluated if this localization to subsynaptic compartments was regulated by the C-terminal sequences of APP, namely, the "YENPTY" domain. Towards this, we found that deletion of C-terminal regions of APP with partial or complete deletion of YENPTY, namely, APP-Δ9 and APP-Δ14, affected the lateral diffusion and nanoscale segregation of APP. Lateral diffusion of APP mutant APP-Δ14 sequence mimicked that of a detrimental Swedish mutant of APP, namely, APP-SWE, while APP-Δ9 diffused similar to wild-type APP. Interestingly, elevated expression of PICALM differentially altered the lateral diffusion of the APP C-terminal deletion mutants. These observations confirm that the C-terminal sequence of APP regulates its lateral diffusion and the formation of reversible nanoscale domains. Thus, when combined with autosomal dominant mutations, it generates distinct molecular patterns leading to onset of Alzheimer's disease (AD).
Topics: Humans; Amyloid beta-Protein Precursor; Alzheimer Disease; Arthrogryposis; Mutation; Risk Factors; Monomeric Clathrin Assembly Proteins
PubMed: 37726569
DOI: 10.1007/s00018-023-04939-w -
Cell & Bioscience Sep 2023Sleep disorders (SDs) are a symptom of the prodromal phase of neurodegenerative disorders that are mechanistically linked to the protein α-synuclein (α-syn) including...
BACKGROUND
Sleep disorders (SDs) are a symptom of the prodromal phase of neurodegenerative disorders that are mechanistically linked to the protein α-synuclein (α-syn) including Parkinson's disease (PD). SDs during the prodromal phase could result from neurodegeneration induced in state-controlling neurons by accumulation of α-syn predominant early in the disease, and consistent with this, we reported the monomeric form of α-syn (monomeric α-syn; α-syn) caused cell death in the laterodorsal tegmental nucleus (LDT), which controls arousal as well as the sleep and wakefulness state. However, we only examined the male LDT, and since sex is considered a risk factor for the development of α-syn-related diseases including prodromal SDs, the possibility exists of sex-based differences in α-syn effects. Accordingly, we examined the hypothesis that α-syn exerts differential effects on membrane excitability, intracellular calcium, and cell viability in the LDT of females compared to males.
METHODS
Patch clamp electrophysiology, bulk load calcium imaging, and cell death histochemistry were used in LDT brain slices to monitor responses to α-syn and effects of GABA receptor acting agents.
RESULTS
Consistent with our hypothesis, we found differing effects of α-syn on female LDT neurons when compared to male. In females, α-syn induced a decrease in membrane excitability and heightened reductions in intracellular calcium, which were reliant on functional inhibitory acid transmission, as well as decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) with a concurrent reduction in action potential firing rate. Cell viability studies showed higher α-syn-mediated neurodegeneration in males compared to females that depended on inhibitory amino acid transmission. Further, presence of GABA receptor agonists was associated with reduced cell death in males.
CONCLUSIONS
When taken together, we conclude that α-syn induces a sex-dependent effect on LDT neurons involving a GABA receptor-mediated mechanism that is neuroprotective. Understanding the potential sex differences in neurodegenerative processes, especially those occurring early in the disease, could enable implementation of sex-based strategies to identify prodromal PD cases, and promote efforts to illuminate new directions for tailored treatment and management of PD.
PubMed: 37710341
DOI: 10.1186/s13578-023-01105-4 -
Neuropharmacology Dec 2023Physical inactivity is a global epidemic. People who take the initiative to exercise will feel pleasure during the exercise process and stick with it for a long time,...
Physical inactivity is a global epidemic. People who take the initiative to exercise will feel pleasure during the exercise process and stick with it for a long time, while people who passively ask for exercise will feel pain and cannot stick with it. However, the neural mechanisms underlying voluntary and forced exercise remain unclear. Here, we report that voluntary running increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSC) but decreased membrane excitability in D1R-MSNs, whereas D2R-MSNs did not change in mEPSC and membrane excitability. Forced running increased the frequency of mEPSC and membrane excitability in D2R-MSNs, but D1R-MSNs did not change, which may be the mechanism by which forced exercise has a non-rewarding effect. These findings provide new insights into how voluntary and forced exercise mediate reward and non-reward effects.
PubMed: 37690678
DOI: 10.1016/j.neuropharm.2023.109714